Compound Delivery Tube

ABSTRACT

A tube for selective administration of a compound.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/045550, filed Oct. 26, 2001 which is a divisional of U.S. patentapplication Ser. No. 09/692,857, filed Oct. 20, 2000. This applicationalso claims priority to U.S. Provisional Patent Application Ser. No.60/161,130, filed Oct. 22, 1999, and to U.S. Provisional PatentApplication No. 60/170,051, filed Dec. 9, 1999. All of theseapplications are incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates generally to the field of a tube with an internallayer comprising a polymer matrix and a captured compound, and moreparticularly to an apparatus for releasing a compound into anintravenous environment such as during intravenous drug administration.

BACKGROUND OF THE INVENTION

Invasive drug administration can be a difficult procedure to alter, onceit is initiated. The dynamic nature of drug administration can bedifficult to anticipate. Feedback mechanisms can be used to monitor drugadministration and exert control mechanisms on the system.

As drugs are becoming more sophisticated and endogenous compoundscontinue to be discovered and synthesized, mechanisms to deliver drugsin a more exact and versatile fashion will allow for fuller drug utilityto be realized.

Drugs have been released at the tip of solid catheters by applying laserenergy as an aid in tumor or local drug therapy. Compounds have beenencapsulated with the anticipation of releasing them in a controlled wayfor many years in the form of timed release capsules, matrix embeddedtablets, or controlled release granules. A catheter product existswhereby an interior coating of antibiotic provides prophylacticprotection against infection by providing zero order release of drugfrom the interior surface.

Standard drug infusion consists of employing infusate of constantconcentration with respect to an active compound. The volumetric flowrate determines the rate at which a drug or compound is delivered to thesystemic circulation or organ system. Altering the rate of drug deliverynecessitates altering the volumetric flow rate of the infusateapparatus. Various catheter designs and drug delivery systems aredescribed in U.S. Pat. Nos. 5,304,121; 5,482,719; 6,086,558; 5,991,650;5,795,581; 5,470,307, 5,830,539; 5,588,962; 5,947,977; 5,938,595;5,788,678; 5,868,620; 5,843,789; 5,797,887; 5,773,308; 5,749,915;5,767,288; and 5,665,077.

The present invention overcomes the shortcomings of previous designs andsystems in a novel and unobvious way.

SUMMARY OF THE INVENTION

One aspect of the present invention relates to a method for providing acompound into a first flowing material. The method includes providing asection of tubing having an interior with a layer of a second matrixmaterial bonded to the interior, releasably capturing a first compoundin the second matrix material, and flowing the first material throughthe interior and over the second matrix material. Energy is applied tothe second matrix material, and the first compound is released from thesecond matrix material into the first flowing material.

In another aspect, the present invention includes a flexible outersheath with an interior surface and an exterior surface. A polymermatrix is attached to the interior surface of the sheath, the polymermatrix defining a lumen therethrough for flow of the liquid. Atherapeutic agent is releasably captured by molecules of the polymermatrix.

Another aspect of the present invention includes a method formanufacturing a catheter. The method includes providing a sheath with aninterior surface, and applying a layer of matrix material onto theinterior surface. The matrix material is in a swelled condition. A rodis inserted into the interior of the flexible sheath. The flexiblesheath is formed into a predetermined shape, and volume of the polymermatrix is shrunk. The rod is removed.

Another aspect of the present invention concerns a method formanufacturing an internally coated tube. The method includes providing arod and a sheath with an interior surface and an exterior surface. Themethod further comprises applying a layer of a polymer matrix onto thesurface of the rod, and placing the rod within the interior of thesheath. The method includes forming the sheath into a predeterminedshape around the rod and removing the rod from the formed sheath.

Another aspect of the present invention concerns a method for providinga therapeutic agent to a biological unit. The method includes providinga compound releasably captured within a matrix material, the compoundbeing releasable upon receiving an energy input. The method includesplacing the matrix material and captured compound in fluid communicationwith a fluid which flows in a biological space of the biological unit.Energy is provided to the matrix material sufficient to release aportion of the compound, and the compound is released into thebiological unit in an irregular pattern.

These and other aspects of the present invention will be apparent fromthe description of the preferred embodiment, the claims, and thedrawings to follow.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of a prior art system fordelivering a drug by a catheter into a patient.

FIG. 2 is a schematic representation of one embodiment of the presentinvention for providing a therapeutic agent into a biological unit by acatheter.

FIG. 3 is a cross-sectional view of the catheter of FIG. 2 as takenalong section 3-3 of FIG. 2.

FIG. 4 is a cross-sectional view of FIG. 3 including the designation ofdiameters for calculation of the amount of therapeutic agent within thepolymer matrix.

FIG. 5A is a section of a catheter according to another embodiment ofthe present invention.

FIG. 5B is a section of a catheter according to another embodiment ofthe present invention.

FIG. 6 is a schematic representation of a closed-loop system forproviding a therapeutic agent to a biological unit.

FIG. 7 is a schematic representation according to another embodiment ofthe present invention for providing a therapeutic agent to a biologicalunit in a fractally-based pattern.

FIG. 8 is a perspective view according to another embodiment of thepresent invention for manufacturing a catheter assembly.

FIG. 9 is a perspective view of the assembly of FIG. 8 with the sheathclosed around the rod.

FIG. 10 is a schematic representation according to another embodiment ofthe present invention for withdrawal of fluid from a biological unit andreturn of the fluid to the unit.

FIG. 11 is a schematic representation according to another embodiment ofthe present invention for withdrawal of fluid from a biological unit.

FIG. 12 is a schematic representation according to another embodiment ofthe present invention.

FIG. 13A is a graphical representation of the log of a spectral densityverses the log of frequency.

FIG. 13B is a graphical representation of the quantity of magnitudesampled at six regular intervals.

FIG. 13C is a graphical representation of the quantity of durationsampled at six regular intervals.

FIG. 13D is a graphical representation of the quantity of intervalsampled at six regular intervals.

FIG. 13E is a graphical representation of a time history of fractallyderived pulses synthesized from the quantities represented in FIGS. 13B,13C, and 13D.

DESCRIPTION OF THE PREFERRED EMBODIMENT

For the purposes of promoting an understanding of the principles of theinvention, reference will now be made to the embodiments illustrated inthe drawings and specific language will be used to describe the same. Itwill nevertheless be understood that no limitation of the scope of theinvention is thereby intended, such alterations and furthermodifications in the illustrated devices, and such further applicationsof the principles of the invention as illustrated therein beingcontemplated as would normally occur to one skilled in the art to whichthe invention relates.

All documents, including patents, books and other publications, namedherein are incorporated herein to their complete extent by reference.

Turning first to FIG. 1 there is shown a typical infusion apparatus 1000commonly in use in most modern hospital settings. This apparatusadministers infusate 1005 systemically to a patient 1007. Infusate fluid1005 is contained in a plastic bag 1010, and the fluid is allowed topass at some predetermined volumetric flow rate through plastic tubingand catheter setup 1015 and into an appropriate biological space,usually vascular. This space could be other body spaces or cavitiescapable of accepting positive volumetric flow, such as the peritoneum orcerebral spinal fluid space. This defines an “open” space or cavity asopposed to a closed or site specific location. Examples of other openspaces include the systemic circulation, the cerebral spinal fluidspace, the lymphatic space, synovial fluid spaces and urinary fluidspaces.

Administration of a compound or drug 1020 is accomplished in severalways. For example, the drug 1020 may be manually injected by anattendant through a hand syringe 1025 that is in fluid communicationwith catheter 1015. As another example, a pump 1030 containing aquantity of drug 1020 pumps a controlled quantity of the drug into anapparatus that is in fluid communication with catheter 1015. Maximummaintenance of the sterile environment of the system is realized

The amount of drug administered is directly related to the infusate flowrate and the concentration of compound (drug) in solution with theinfusate. Changing the rate of infusion of drug necessitates changingthe volumetric flow rate of infusate through the catheter in directproportion to the desired change in drug administration. Once theinfusion setup is operating, generally under sterile conditions,changing the compound or drug for an alternate compound or drug requiresa new infusion setup to be put into operation, with a new reservoir ofinfusate with drug in solution.

The present invention relates to a system including a catheter assemblyand a source of energy for releasing a compound into a biological space,such as the vascular system, peritoneum, cerebral spinal fluid space, orother biological spaces which can accept a volumetric flow rate ofinfusate. According to one embodiment of the present invention, atherapeutic agent such as a drug is linked by photolabile bonds to apolymer matrix surrounding a lumen of a catheter. Infusate fluid such asnormal saline, 5% dextrose and water, lactated Ringer's solution,crystalloid solution, plasma or blood flows through the lumen of thecatheter from a source of the infusate into the biological space. Whenit is desired to release the compound into the biological space, thepolymer matrix surrounding the lumen and including thephotolabily-linked compound is exposed to the energy such as lightradiation. The radiation breaks the photolabile bonds, and the compoundis released from the material such that it can diffuse into theinfusate.

Changing the concentration of infusate without appreciably changing thevolumetric or mass flow rate is contemplated by this invention. Someinfusate apparatus only allow volume dependent alteration of dosingrate, which may be prohibitive to the recipient. It may be difficult toreadily add or change pharmacotherapy due to insufficient veinintegrity. The immediacy of emergency settings may dictate drug to beadministered as readily as possible, or discontinued in as immediate afashion as possible.

The present invention can provide an effective and efficient mechanismto exert an infusate concentration change for a compound delivery systemwith little or no volumetric changes. The clinical setting is animmediate example where compounds can be introduced by varying theconcentration profile of a drug to alter the dose or mass of drugadministered. This is a departure from the traditional manner ofincreasing the volume flow rate of intravenously administered drugs. Theease and rapidity of introducing new compounds to a given drug therapyprovided by the present invention may be unmatched for some settings.In-line prodrug-drug interactions are possible. Developing drugs withpreviously prohibitive delivery characteristics, such as extremely shorthalf-lives, may be delivered with this device.

In a preferred embodiment, the material forming the lumen of thecatheter is a polymer such as a hydrogel, and the one or more compoundsto be released are photolabily-linked to the molecules of the hydrogel.The compound(s) to be released are preferably therapeutic agents whichare released systemically into the biological space. The photolabilelinkages between the compound and the hydrogel are preferably broken byresonating the photolabile bond with the proper wavelength of radiation.In a preferred embodiment, the source of radiation is a laser tuned to aband of wavelengths that will resonate with the photolabile links.However, the present invention also incorporates those embodiments inwhich the source of radiation includes lasers operating over wide rangesof wavelengths and also incoherent light.

Another embodiment of the present invention includes a catheter assemblyincluding a material defining a lumen, a photolabily-linked compoundwithin that material, a source of infusate flowing through the lumen,and a source of energy. The embodiment further includes a sensor forsensing a condition of a biological subject and a controller forreceiving the signal. As one example, a source of radiation, such as alaser, is activated to irradiate the material, break the photolabilebonds, and release the compound into the biological subject upon thesensing of a particular condition. As another example, the sensorgenerates a signal corresponding to the activity of the heart. Thecontroller receives this signal and upon determination that the heart ismalfunctioning controls the laser to release a drug such as a cardiacagent into the infusate, which then flows into the biological space ofthe subject so as to address the heart malfunction.

A wide range of therapeutic agents can be incorporated in complexes forcontrolled release into the systemic circulation or other body cavity ofa biological subject. It is preferable that the chemical structure ofthe therapeutic compound contain a nucleophile group such as carboxylicacid, amino or hydroxyl, which attaches to the light sensitive linkageof the polymer matrix material defining the catheter lumen. Examples ofsuch therapeutic compounds include acetylsalicylic acid (aspirin),indomethacin, nicotinic acid, naproxen, ibuprofen, cimetidine,ranitidine, cycloserine, flucytosine, amantadine, benzocaine, penicillinV, acetaminophen, and cortisone. Classes of drugs amenable to this typeof delivery include, but are not limited to antibiotics, anesthetics,analgesics, cardiac agents, psychotropics, and hormones.

Although what has been described is a catheter flowing infusate, thepresent invention also contemplates the application of a compoundreleaseably captured in a matrix material applied to the inside oftubing, where a flowing material flows through the tubing and over thematrix material. The flowing material may be a fluid, such as a liquidor a gas and can also be a flow of solid particulate matter such as anaerosol or solid microparticles. Further, the matrix material forreleaseably capturing a compound is preferably a polymer material, butcan also be other types of matrix material. The compound releaseablycaptured in the matrix can be a therapeutic agent, but can also be anycompound capable of being releaseably captured in the matrix.

As used herein, the term “catheter” includes those meanings anddefinitions and understandings used by one of ordinary skill in the art,but also includes tubing for withdrawal of bodily fluid from abiological unit. Further, the term “therapeutic compound” as used hereinrefers to drugs and compounds administered to biological units, and alsorefers to drugs and compounds used to condition fluids withdrawn from abiological unit. The use of a prime (′) designation with a numberindicates that the element shown or described is the same as thenon-prime element, except as shown or described differently.

Turning to FIGS. 2 and 3, a catheter is constructed to release atherapeutic compound 65 into the infusate 24 flowing in the catheter 20during the infusion process. In one embodiment, the catheter size issimilar to conventional vascular catheters used in hospitals of today.As used herein, the term catheter includes any generally tubular medicaldevice for insertion into canals, vessels, passageways, or body cavitiesfor the reception or withdrawal of fluids through the catheter lumen. Acatheter, according to the present invention provides additionaltherapeutic properties to the infusate 24 as it travels through thecatheter lumen space 60. Conventional catheter designs that may beadapted for delivery of a therapeutic agent according to the inventionsdescribed herein include, but are not limited to, percutaneoustransluminal angiography (PTA) catheters, percutaneous transluminalcoronary angioplasty (PTCA) catheters, vascular and peripheral vascularcatheters, thrombectomy catheters, renal catheters, esophagealcatheters, perfusion catheters, upper and lower gastrointestinalcatheters, bile duct and pancreatic duct catheters, urogenitalcatheters, and similar catheters both with and without dilationcapabilities. Devices used for long-term vascular access may be adaptedfor use with the present invention. These catheters include, but are notlimited to totally implantable intravascular devices (TIDs), tunneledcentral venous catheters including Hickman, Broviac, Groshong, andQuinton, which are commonly used to provide vascular access to patientsrequiring prolonged IV therapy (e.g., chemotherapy, home infusiontherapy, hemodialysis).

FIG. 2 schematically depicts a system 15 according to one embodiment ofthe present invention. System 15 includes a catheter assembly 20 whichprovides a flow of infusate 24 from an infusion apparatus 25, such as agravity drip bag, into the open biological space of a biological unit30, such as into the vasculature of a patient. An energy source 35 iscoupled by an appropriate conduit 40 into catheter 20. Energy source 35provides energy through conduit 40 to a polymer material within catheter20. In one embodiment of the present invention, energy source 35includes a laser, laser controller, and controller interface. The laserprovides coherent light energy to a conduit 40 such as a fiber opticcable to transmit the laser energy into the catheter 20.

FIG. 3 shows a cross-section of catheter assembly 20. Catheter 20includes a sheath 50 forming the basic structure of assembly 20 andcapable of transmitting energy from source 35. Located within theinterior of sheath 50 is a polymer matrix 55 which forms a lumen 60therein. Infusate 24 from infusion apparatus 25 flows through lumen 60into the biological space. Polymer matrix includes within it one or moretherapeutic agents 65 that are held within the polymer matrix 55 untilreleased by energy from source 35. According to one embodiment of thepresent invention, the linkage of the therapeutic agent 65 to thepolymer matrix 55 is accomplished by a covalent photolabile bond. Thetransmission of laser energy through sheath 50 provides energy thatbreaks the photolabile bond to release the therapeutic agent. Thetherapeutic agent then defuses according to Fick's Law through thepolymer matrix and into the infusate flowing within lumen 60. In thismanner the therapeutic agent can be stored within polymer matrix 55until it is desired to release therapeutic agent 65 into the biologicalunit. For those embodiments of the present invention utilizing a sourceof energy such as a laser, sheath 50 includes one or both of areflective coating 70 and/or an opaque coating 75.

Although what has been shown and described is a catheter 20 extendingfrom a source 25 of infusate into the vasculature system of a biologicalunit, the present invention also contemplates the use of a catheter 20which is linked as an input to a separate catheter, such as catheter1015. The separate catheter may be made of any size and shape whichfacilitates entry of the separate catheter into the biological unit. Theseparate catheter and catheter 20 are joined in a union outside of thebody of the biological unit. This alternate embodiment permits catheter20 to have an outer diameter and/or use materials not compatible withentry into a biological unit.

A catheter assembly 20 according to one embodiment of the presentinvention has both drug storage and drug releasing properties, and theability to transmit appropriate energy from a source of energy 35 intopolymer matrix 55. A photo-activateable therapeutic agent deliverymaterial is used, in which a therapeutic agent 65 is combined bycovalent bonding, incorporation in a matrix, or encapsulation, with aphotosensitive macromolecule. In this combination, the drug is inert.The macromolecule is large enough to prevent migration of thecombination within the catheter body, so that the combination can be inplace during infusion or withdrawal of bodily fluids through the luminalspace. A drug or other compound is released from the combination, in anactive form, upon appropriate stimulation by the source of energy 35.

The drug may be combined with the polymer matrix using any of severalmechanisms including photolabile chemical bonding, physical dispersion,or encapsulated or embedded in layers of photodegradable polymers. Inpreparing the covalent chemical complex of this aspect of the presentinvention, it is preferred to link the photolabile compound to thepolymer 55 first, and to link the drug 65 to the photolabile groupsthereon subsequently. Coupling of the polymer 55 to the photolabilelinking compounds suitably takes place in solution, as does thesubsequent coupling of the photolabile linking compounds to thetherapeutic agent.

A wide choice of polymers 55 are available for this purpose. It isdesirable that the polymer be biochemically acceptable and inert. It isfurther desirable that the polymer should possess chemical groupscapable of reaction with a functional group of the photolabile compoundsuch as the carboxylic acid group of BNBA or CPA, e.g. hydroxyl groups.It should also be capable of releasing the active drug freely, once thecovalent chemical bonding has been broken. For example, the drug 65should be able to diffuse out of the residual polymer matrix in thepresence of infusate fluid. Examples of suitable polymers 55 include,but are not limited to polyvinyl alcohol (PVA), polyethylene oxide(polyethylene glycol PEG), acrylamide copolymers, vinylpyrrolidonecopolymers, hydroxyl functionalized polylactides, poly (hydroxyethylmethacrylate) (HEMA), copolymers of two or more such monomers, e.g.copolymers of vinylpyrrolidone and HEMA, and copolymers of ethyleneoxide and propylene oxide. The hydrogel polymer may also be selectedfrom the group consisting of polycarboxylic acids, cellulosic polymers,gelatin, polyvinylpyrrolidone, maleicanhydride polymers, polyamides,polyvinyl alcohols, and polyethylene oxides or polyacrylic acid.

The catheter sheathing material is a homogeneous fiber optic materialthat is transparent to and is able to conduct the controlling energy,preferably laser light, throughout the extent of the molded sheath. Thefiber optic material is of a type known to the art of laser cathetersand is configured to transmit laser energy. A person of ordinary skillin the art can readily adapt known fiber optic materials forincorporation into the apparatus of the present invention. A hydrogelmatrix forms a large portion of the body of the catheter tubing and istenaciously affixed to the inner surface of the energy-conductingsheath. This matrix provides the storage space for photolabily linkedcompound to remain in a soluabilized and bound state prior to compoundrelease via controlled delivery of energy through the sheathingmaterial.

The hydrogel polymer matrix 55 deposition and affixation to the innersurface 52 of the catheter sheath 50 can be accomplished by thefollowing example according to U.S. Pat. No. 5,304,121, incorporatedherein by reference. The inner surface 52 of the catheter sheath 50 iscoated with a solution of 4,4′ diphenylmethane diisocyanate (MDI) inmethylethylketone for 30 minutes. After drying in an air oven at 85° C.for 30 minutes, the sheath is dipped in a 1.7% solution of poly(acrylicacid) homopolymer having a molecular weight of about 3,000,000 indimethylformamide (DMF) and tertiarybutyl alcohol. After drying at about85° C. for 30 minutes, a smooth coating is obtained. The sheath is ovendried for 8 hours at 50° C. One function of the drying steps is toremove solvent from the coating. The polyisocyanate solution is at aconcentration of about 0.5 to 10% by weight. The polyacrylic acid is ata concentration of about 0.1 to 10% by weight. The poly(carboxylic acid)to polyisocyanate molar ratio is generally about 1:1. The formation ofthe hydrogel is well known in the art, such as the hydrogel furtherdescribed in U.S. Pat. No. 5,091,205, incorporated herein by reference.

The rate of drug release is controlled by exposure of the catheter bodyto a source 35 of transmissible energy, such as the energy of a laser.Persons of ordinary skill in the art know readily available electronicdevices which can be used for laser energy generation and computercontrol. Through suitable optical coupling 40, the laser energy entersthe catheter sheath or casing 50, and in a preferred embodiment, isreflected off of the reflective outer coating 70 and is transmitted intoand through the catheter body when it is desired for drug to be releasedfrom catheter matrix material storage. Photolabile bonds are broken andthe freed therapeutic agent 65′ is released and traverses across theinfusate soluble polymer matrix material 55, and into the catheter lumen60 as free therapeutic agent in infusate solution 24. An outer opaquecoating 75 with reflective properties prevents extraneous light fromentering the catheter body and also directs the controlled laser lightinto the catheter body to provide energy exposure.

Energy for release of the drug in its active form from the drug-polymercombination can be by one of a variety of means depending upon thephotosensitivities of the chosen photolabile bond, the polymer 50, andthe drug 65. For example, the source 35 of energy can be radiation suchas infrared, visible, or ultraviolet radiation, supplied fromincandescent sources, natural sources, lasers including solid statelasers, or even sunlight. In one embodiment, the present inventioncontemplates the use of a source 35 of coherent light of wavelengthsfrom about 300 nm to about 1200 nm. This includes UV, visible andinfrared light. The choice of wavelength is based on the photolabilecharacteristics of the bonds holding 65 within 55 and is selected tomatch the wavelength necessary to break the photolabile bond between 65and 55. Since body tissues tend to absorb radiation in the ultravioletregion of the electromagnetic spectrum, it is preferred to choose aphotolabile bond sensitive to red and infrared wavelengths. The amountof drug released is proportional to the dosage of the radiation. Variousagents for producing the photolabile bonds are described in related aresuch as U.S. Pat. No. 5,767,288, incorporated herein by reference.

Administration of the radiation can be by use of fiber optic light pipesor sheathing included within the catheter assembly. Fiber optic lightpipes 40 are known and used in various types of medical treatments, forexample irradiation treatment of internal body organs such as bladderirradiation. In some embodiments of the present invention, a fiber opticlight pipe also acts as the main source of energy into matrix 55, thelight pipe providing light down the length of catheter 20 andtransmitting the light radially or longitudinally through the cathetersheath. These light pipes can be used to couple energy of particularwavelengths to distinct sections of the sheathing material.

Preferably, the apparatus comprises an optically transmitting fiberoptic outer sheath 50 having a proximal end and a distal end. Thematerial can be either transparent or translucent. The preferredmaterial is transparent and non-distendable. The fiber optic sheath 50is of a type known in the art of laser catheters and is configured totransmit laser energy. The intensity and overall uniformity of the lighttransmitted can be dramatically increased by using a coating 70 thatreflects and/or scatters light into the lumen 60. The sheath 50preferably includes a reflective outer coat 70 that reflects andscatters light into and through the polymer matrix 55 and into the lumen60, providing a diffuse reflection of the light striking the matrix 55and agent 65. The function of the reflective material is to provideincreased uniformity and efficiency in the light transmitted throughpolymer matrix 55. Examples of material for coating 70 include, but arenot limited to, titanium dioxide, aluminum, gold, silver, and dielectricfilms. A person of ordinary skill in the art can readily adapt knownreflective materials for incorporation into the outer portion of theapparatus of the present invention. The preferred reflective materialwill reflect and scatter light and prevent from about 20% to 100% oflight striking the material from passing through the material. The mostpreferred will reflect and scatter over 70% of the light. The reflectivematerial can be incorporated onto the outer portion of the sheath 50 ina variety of ways. For example, the reflective material can be appliedto the outer surface of catheter sheath 50 after the catheter is formed,by using a dipping process. Alternatively, the reflective material canbe directly incorporated into the material used to form the cathetersheath 50 during the manufacturing. The method used to incorporate thereflective material into the catheter is based primarily on thereflective material used, the material the catheter is made of, and themethod used to manufacture the catheter. A person of ordinary skill inthe art can readily employ known procedures for incorporating areflective material within or onto the surface of the catheter sheath50.

In addition to a reflective coating, the catheter may further have anadditional opaque coating 75 over the reflective coating 70. An opaquecoating 75 is used to further prevent light from exiting the catheterexterior surface or extraneous light from entering the body of thecatheter. Some catheters, such as those disclosed by Overholt et al.Lasers and Surgery in Medicine 14:27-33 (1994), utilize an opaqueabsorbing coating, such as black Color Guard supplied by PermatexIndustrial Corp. Avon, Conn., to prevent the light from beingtransmitted through portions of the catheter.

Some embodiments of the present invention further include one or moreoptical sensors 80. Optical sensors 80 are integral to the catheter andused to measure the intensity of illumination when the catheter is usedtherapeutically. Optical sensors 80, such as a fiber optic probe or aphotodiode as part of a balloon catheter, have been described in U.S.Pat. No. 5,125,925, incorporated herein by reference. By monitoring,with a sensing fiber on the wall of the fiber optic sheath, the light towhich the sensing fiber and, hence, the catheter matrix are exposed, canbe determined. Individual light doses and accurate measurement of thecumulative light doses are measured by processor 85 and provide anaccurate measurement of the cumulative light dose and relates toreleased compounds from various sections of the catheter matrix orassociated sections of the catheter matrix. Light power output is alsomonitored and alarm may be given in the event of abnormal lightconditions.

In accordance with the present invention, therapeutic agent 65 is storedwithin the polymer matrix 55. Once the infusate is flowing through lumen60 at a constant rate and the matrix is in a hydrated condition, thetherapeutic agent 65 is in a soluablilized state within the polymermatrix, with respect to the surrounding infusate fluid infiltrate. Abarrier to complete drug solution in the infusate are laser liable bondsholding the therapeutic agent 65 within the polymer matrix 55. Thesebonds can be broken when exposed to the proper frequency and intensityof laser energy, thereby freeing the drug to enter the catheter lumen60.

The amount of storage volume is adequate to incorporate a substantialamount of drug to be used for various procedures. As best seen in FIG.4, in one embodiment of the present invention the inner wall 52 ofsheath 50 has a diameter D₂ of about 3.6 mm, and the lumen formed bypolymer matrix 55 has a diameter D₁ of about 2.6 mm. The total length L₁of the portion of the catheter 20 incorporating the polymer matrix is1.7 meters. The cross-sectional area A₁ is calculated as π(D₂ ²-D₁ ²)/4and is 4.84 mm². The total volume V₁ of the polymer matrix is 8.23 cm³.This is a representative volume calculation and provides an estimate ofa catheter body matrix 55 volume that would be available for drugincorporation for the present invention. There is no general restrictionof the tubing diameter of the portion of the present invention thatresides outside the vasculature. It is anticipated that an 8-12 cm³volume of catheter matrix material 55 would be sufficient to incorporatesubstantial amounts of drug(s) into the polymer matrix for delivery intothe infusate and further into the systemic circulation or receiverspace. Much larger reservoirs for drug storage can be realized forportions of the present designed to be extravascular in nature. Bycontrolling the concentration of the therapeutic agent 65 within matrix55, the total amount of therapeutic agent 65 available for infusion canbe limited by control of the thickness and length of the polymer matrix.For example, the total amount of therapeutic agent stored in aparticular catheter assembly 20 can be limited to an amount that is safefor delivery under any conditions. Jacketed conditioning of the tubingextravascularly, such as for temperature or radiation exposure, can alsobe provided for extravascular portions of the present invention to allowfor better inline processing of fluids or for maintaining the integrityof the catheter body matrix or compounds stored therein.

FIG. 6 depicts a system 100 for the automatic administration of atherapeutic agent based on a sensed response from a biological unit. Abiological unit 30 such as an animal produces a response which can besensed by a sensor 105. The response elicits an output signal 107 whichis provided to a signal processor 110. Signal processor 110 preferablyaccepts analog signal 107, and includes suitable A/D processing and aninternal digital processor which produces a control signal 112 to energysource 35, such as a laser. In response to control signal 112, energysource 35 produces an energy output 120 which is coupled into catheter20. Energy response 120, which is preferably a controlled amount oflaser light, is transmitted down the fiber optic sheath 40 of catheterassembly 20 and fractures the bonds between the therapeutic agent 65 andpolymer matrix 55. The release of the therapeutic agent into theinfusate and subsequently into the biological unit 30 changes theresponse of the biological unit that resulted in the signal 107generated by sensor 105. Another example, sensor 105 measures the brainactivity of a person during anesthesia and provides a signal to anelectroencephalographic monitor 110. If the depth of anesthesia isdetermined through brain wave activity to be aberrant, then a signal issent to a power supply to fire a laser and release a therapeuticanesthetic agent from the catheter into the blood stream of the patient.

As one example, sensor 105 measures the cardiac activity of a person andprovides a signal to a cardiac monitor 110. If the cardiac monitor 110determines that the patient is in cardiac distress, then a signal issent to a power supply to fire a laser and release a therapeutic cardiacagent from the catheter into the blood stream of the patient.

The present invention may be used during outflow of bodily fluids from abody cavity. FIGS. 10 and 11 schematically depict systems for thewithdrawal of bodily fluids from a biological unit. The exit of fluidfrom the body during kidney or peritoneal dialysis would be examples ofthis use. A device 310 for withdrawal of fluids, such as dialysismachine, is in fluid communication with catheter 20 a. A compoundcaptured within the polymer matrix of catheter 20 a is released byenergy from energy source 35 a as transmitted along conduit 40 a. Thebodily fluid is further conditioned within conditioning unit 310, whichis in fluid communication with a catheter 20 b for return of the fluidinto the biological unit. Another therapeutic agent captured in thepolymer matrix of catheter 20 b is released into the bodily fluid byactivation of energy source 35 b which provides energy through conduit40 b into the sheath of catheter 20 b.

The catheter or tubing 20 would release compound into contents of bodyfluid, such as, blood, cerebral spinal fluid, cardiac pericardial fluid,lymph, during outflow, adding pretreatment compounds, such asanticoagulant, antibiotic, anti-thrombotic or other conditioning ortreatment agents proximal to entrance into the dialysis or otherequipment. Upon exit from a treatment apparatus, such as dialysis orchemotherapy devices, and prior to return into the living system,further conditioning compounds could be released into the luminal tubingspace to deactivate or activate functionalities in the treated bodyfluids. The advantage of maintaining sterile or otherwise separateconditions during such extra-corporal closed loop treatments isrealized. It is anticipated that the tubing designed from the presentinvention could be incorporated into the interior of an apparatus fordialysis or other inline treatment regimen, such as during lymphatic orlucemic cancer treatment or other disease amenable to fluid treatmentmodalities

The permanent withdrawal of fluids for diagnostic sample collection canbe pretreated during collection with another embodiment of the presentinvention. As seen in FIG. 11, system 400 withdraws bodily fluid from abiological unit and conditions that fluid for subsequent use duringtesting or analysis of the fluid. Fluid is withdrawn from a biologicalunit 30 through a catheter 20 which is in fluid communication with afluid receiver 410, receiver 410 including a suction pump or other meansfor withdrawing fluid. As the fluid passes through catheter 20, energysource 35 provides energy through conduit 40 into the polymer matrix ofcatheter 20, such that a compound releasably captured in the polymermatrix is released into the bodily fluid flowing into receiver 410. Forexample, the bodily fluid can be blood, and the compound released fromthe polymer matrix can be an anticoagulant. Addition of anticoagulant,antibodies, or dyes prior to sample preparation can aid in the accuracy,reliability and speed of such clinical testing. This sample conditioningcould extend to any sample fluid obtained through such tubing, includinglymph, CSF, certain biopsy material and urine. It is also anticipatedthat various laboratory, experimental, industrial or non-biologicalprocesses or settings can incorporate the present invention and methodthereof for the purposes of adding compounds to an inline process.

It has been shown (U.S. Pat. No. 5,482,719) that a shape retainingnon-flowing aqueous hydrogel polymer and drug compound PEG6000-BNBA-nicotinic acid released unchanged nicotionic acid uponirradiation with light. The anti-viral drug adamantamine was coupled toa polymer via a photolabile chemical linkage utilizing the amino groupof the drug, and then released in unchanged form by photolysis 8 mg ofthe 10 mg of adamantamine combined with the hydrogel-photolinker presentin the formed hydrogel-linker-drug yield of ADANABA-Et. This complexreleased unchanged adamantamine over a ten minute period with most ofthe drug being released within 5 minutes and with only a trace amountleft complexed after ten minutes of irradiation.

The present invention also contemplates non-biological embodiments. FIG.12 is a schematic representation of system 500 according to anotherembodiment of the present invention for releasing a compound into afluid flowing from one container into another container. A fluid 524held within a container 525 is removed from container 525 by a pump 521.The pump 521 provides the fluid to a section of tubing 520 whichcontains an internal layer of a matrix material which includes areleasably captured compound. Application of energy from source 535through conduit 540 into the matrix material results in the release ofthe compound into the flowing fluid 524. The released compound is addedto the flowing fluid without appreciably changing the volumetric or massflow rate of the flowing fluid 524. The mixture 527 of the flowing fluidand compound flows into container 526.

The section of tubing 520 containing the releasably captured compoundand the matrix material is the same as catheter assembly 20, except asshown and described differently. The sheath material for tubing 520 doesnot need to be either biocompatible nor flexible and may be constructedfrom any material which transmits the energy into the matrix material.The compound releasably captured within the matrix of tubing assembly520 does not need to be biocompatible or provide therapeutic affect, andmay be any material which can be releasably captured within the matrixmaterial and subsequently released by the application of energy to thematrix material. Energy source 535 is the same as energy source 35,except as shown and describe differently. Energy source 535 does notneed to be biocompatible in terms of the quantity or quality of energyreleased.

Another embodiment of the present invention relates to a method formanufacturing a catheter assembly. The catheter includes one end that isreadily attachable to a laser or non-laser light source. FIGS. 8 and 9depict a molded outer sheath 50′ of laser light conductible fiber opticmaterial and incorporating multiple baffles 253 and 254 to center aninner rod 252 used during assembly of the catheter. Baffles 253 and 254are semicircular in shape and are integrally molded into sheathing 50′.Each baffle preferably includes a semicircular cut out 257 and 258,respectively. These cut outs are shaped to accept and support a formcoated with polymer matrix, such as rod 252 coated with hydrogel 55.

The light carrying section of the outer fiber optic sheath 50 and 50′can be of any thickness that conducts the proper intensity of light. Thepreferred fiber optic sheath will have a cross sectional area from about200 to about 3000 microns and preferably about 1200 microns. The choiceof the sheath cross sectional area depends on the brightness of thelight source and the optical power output required for release of thedrug from polymer matrix. In some embodiments, the sheath provides thestructural integrity and flexible characteristics of the overallcatheter tubing. This material is readily available to one of ordinaryskill in the art

As shown in FIGS. 8 and 9, the catheter sheath 50′ is a split cylinder,with the split occurring lengthwise along the sheath. The sheathincludes only a single split 251, such that the sheath 50′ preferablyremains one piece. In some embodiments of the present invention, themolded sheath includes a hinge section 280, such as and area of weakenedmaterial, on the side of the sheath opposite the split. This hinged area280 facilitates a bending apart of the two lengthwise sections of themolded sheath 50′. The two sections can be hinged away from one anotherso as to facilitate the later insertion of a rod 252 in the central cutout of the baffles.

A biocompatible hydrogel polymer matrix 55 which includes thephotolabily bonded therapeutic agent 65 is deposited upon a rod 252designed to loosely bind the gel material. The rod is composed of amaterial such as a hard plastic. The surface does not bind tightly tothe gel, which may be property of the hard plastic itself or a propertyof a rod coating substance such as TEFLON® provided to coat the surfaceof the rod. The polymer 55 thickness is allowed to build up in thehydrated state around the rod 252 to a thickness such that the volume ofthe matrix 55 and rod 252 together become greater than the internalvolume of the closed catheter sheathing. Various sections of hydrogelmaterial may be included such that each section might incorporate uniquecompounds or groups of compounds distinct from other sections withregard to their confinement properties and releasing characteristics.

The sheath is formed around the rod-hydrogel section, as seen in FIG. 9.The bent-apart sheath sections are brought back into contact, which mayresult in a partial squeezing out of some of the hydrogel in therapeuticagent. The lengthwise split 251 is sealed by a method such as adhesionwith a bonding agent or ultrasonic welding. The inner surface 52′ of thesheath 50′, including the baffles 253 and 254, are preferably preparedto accept the hydrogel via adhesive preparation according to U.S. Pat.No. 5,304,121 and designed to accept the hydrogel 55 and affix it to thecatheter sheath interior prior to assembly with the rod-gel section.

The assembly is allowed to dry, the subsequent dehydration causing thethickness of the hydrogel to decrease by as much as a factor of 6-10.This substantial reduction in volume permits the hydrogel to pull awayfrom the surface of rod 252, since the adhesion of the hydrogel to therod surface is less than the adhesion of the hydrogel to the innersurface 52′ of the sheathing 50′. The rod 252 is then removed, and thesheath is coated on the outer surface with an opaque and reflectivecoating combination 70 and 75. These coatings can also incorporate asealer to provide a means to close the seam 251 remaining after thesheath circumscribes the rod-hydrogel section, or a separate step may beneeded to close the seam prior to coating. When rehydrated during usethe polymer matrix 55 swells and reforms to a shape that allows a lumen60 to form with a diameter generally determined by the central cut-outsof the baffle and the outer diameter of the rod. Appropriate sterileprocedures are followed for tubing that is manufactured for parenteraluse, such that either suitable sterilization techniques compatible withthe catheter materials are followed for components prior to assembly orappropriate post-manufacturing sterilization procedures are carried out,such as radiation bombardment.

Another embodiment of the present invention contemplates a catheterassembly incorporating two different therapeutic agents 65 and 66 whichare not mixed within the polymer matrix, and are separated intodifferent sections of the catheter. As best seen in FIG. 8, a portion 55a of the polymer matrix including captured therapeutic agent 65 coats afirst portion of rod 252. A portion 55 b of the polymer matrix includingcaptured therapeutic agent 66 coats a second portion of rod 252. Ascoated road 252 is placed within the baffle cut outs, therapeutic agent65 is largely confined to section 259 a of sheath 50′, defined betweenbaffles 254 a and 254 b, and between baffles 253 a and 253 b.Therapeutic agent 66 is largely confined to section 259 b of sheath 50′,defined between baffles 254 b and 254 c, and between baffles 253 b and253 c. An arbitrary number and placement of such said sections can beincorporated into the sheath of the present invention. Further, thesesheath sections can be supplied by separate laser light pipes capable oftransmitting multiple distinct wavelengths of laser energy

According to another embodiment of the present invention, catheter 20 ismanufactured using a split, bent-apart, molded sheath 50′, Sections of apolymer matrix such as 55 a and/or 55 b are placed within the interiorsections 259 a or 259 b of sheath 50′. A rod 252 which is preferably notcoated with a polymer matrix is placed within sheath 50′, preferablybeing supported within the cutouts 257 or 258 of the baffles. Theinterior surface 52′ of sheath 50′ is preferably coated as previouslydescribed to improve the adhesion of the polymer matrix to surface 52′.Sheath 50′ is then formed around rod 252, with split 251 being adheredclosed as previously described. The polymer matrix is then shrunk involume, such as by dehydrating. Rod 252 is removed from the closedsheath. Sheath 50′ can include a first section 259 acontaining a firstreleaseably captured compound 65, and a second section 259 b containinga second releaseably captured compound 66.

According to another embodiment of the present invention, catheter 20 ismanufactured using an injection method. A sheath 50 which is not splitalong its length is preferably supported along the outer diameter of itslength in a straight, linear fixture. A rod 252 is held by its ends inthe approximate center of the sheath. A quantity of polymer matrix 55 aand/or 55 b is injected into the annulus between the interior wall 52 ofthe sheath and the outer diameter of rod 252. The interior surface 52 ofsheath 50 is preferably coated as previously described to improve theadhesion of the polymer matrix to surface 52. The polymer matrix is thenshrunk in volume, such as by dehydrating. Rod 252 is removed from thesheath.

In accordance with another embodiment of the present invention, FIG. 5Ashows a cross-section of an apparatus 220 which is the same as catheter20, except as herein described and depicted. In apparatus 220, polymermatrix 55 includes molecules photolabily bonded to two differenttherapeutic agents 65 and 66. These agents 65 and 66 may representdistinctly different drugs with regard to, but not limited to, suchproperties as drug pharmacological classification and storageconcentration within the catheter body. Further, the laser liable bondsholding drugs 65 and 66 may or may not be characterized by differentfrequency or intensity of laser liabilities. The use of a coherent laserlight source will be preferable in many applications because the use ofone or more discrete wavelengths of light energy that can be tuned oradjusted to the particular photolytic reaction occurring in thephotolytic linker necessitates only the minimum power (wattage) levelnecessary to accomplish a desired release of agents such as 65 and 66.

Multiple releases of different therapeutic agents or multiple-stepreactions can be accomplished using coherent light of differentwavelengths. Intermediate linkages to dye filters may be utilized toscreen out or block transmission of light energy at unused orantagonistic wavelengths (particularly cytotoxic or cytogenicwavelengths), and secondary emitters may be utilized to optimize thelight energy at the principle wavelength of the laser source.Preferably, light radiation refers to light of wavelengths from about300 nm to about 1200 nm. This includes UV, visible and infrared light.The choice of wavelength will be based on the intended use, namely beingselected to match the activation wavelength for the cleavage of thephotolabile linkage between the catheter matrix material 55 andcompounds 65 and 66 to be released. The art pertaining to thetransmission of light energy through fiber optic conduits or othersuitable transmission or production means to the remote biophysical siteis extensively developed.

This embodiment affords a means of providing selective multi-drugtherapies on demand. The present invention also contemplates the storageof multiple drugs within the matrix. For example, drug 65 and drug 66can be released within the infusate 24 at times which would allowinteraction within the infusate prior to release into the systemiccirculation.

In accordance with another embodiment of the present invention, FIG. 5Bshows a cross-section of an apparatus 222 which is the same as catheter20, except as herein described and depicted. In apparatus 222, polymermatrix 55 includes molecules photolabily bonded to two differenttherapeutic agents 65 and 66. These agents 65 and 66 may representdistinctly different drugs with regard to such properties as drugpharmacological classification and storage concentration within thecatheter body. Further, the laser liable bonds holding drugs 65 and 66may or may not be characterized by different frequency or intensity oflaser liabilities. This interaction could result in a prodrug effect,where drug 65 activates or alters drug 66, or drug 65 and drug 66interact to produce a new drug 67. Then altered drug 66 or drug 67 wouldbe available to the systemic circulation for therapy. This allows forinline synthesis of drugs or compounds that would be otherwise difficultto produce and administer effectively by other means.

The advantages of this device are increased safety to the recipient ofinfused drug through decreased trauma of infusion site innervations andfor maximum maintenance of sterile conditions. Catheters can be used foreither short-term or long-term vascular access. Factors associated withinfusion-related phlebitis among patients with peripheral venouscatheters including site of catheter insertion, experience of personnelinserting the catheter, frequency of dressing change, catheter-relatedinfection, skin preparation, host factors, and emergency-room insertioncould all be decreased from use of the present invention. The presentinvention provides increased safety for general catheter use byproviding a drug or other compound to be made immediately available foruse when needed for adjunctive therapy without adding any extraequipment into the sterile infusion set environment. This is in contrastto the necessity with current practices for an additional catheter to beinserted, a drug solution to be changed, or any of various otheralterations necessary to add adjunctive drug therapy using catheter ortubing system. The present invention provides quicker and accurate drugdelivery of on-demand doses of new or concurrent multi-drug therapies.The present device can be programmed to release drug at a specified timeand in a controlled amount with a degree of accuracy based upon the highdegree of accuracy available through computer control of an energysource. The computer control allows administration of a specified andappropriate amount of intensity and duration of energy exposure,preferably coherent light, to the catheter sheath for subsequent releaseof agents 65 and 66 into infusate solution.

The drug is also released into the catheter lumen which may extend up toand sometimes inside the vasculature setting. A more immediate entranceinto a positive flow body cavity space, such as the systemic circulationcan be realized with the present device, where drug is stored andreleased at the opening of a catheter inside the vasculature. This is incontrast to a current adjunctive processes including providing drug intoa port which has to travel down the catheter tubing and then enter thesystemic circulation. In such cases an attendant is necessary to mix adrug and inject it into the infusion set port, which takes time and addsan element of human error to the process. In some situations a commonsyringe pump apparatus in place to administer the adjunctive drugtherapy. The present invention has few mechanical parts to fail. Theinfusion pump apparatus involves many moving parts which increases therisk of malfunction. Both attendant and syringe pump apparatus therapymodifiers inject an added volumetric input to the flow of infusate,thereby limiting their effectiveness if the total flow rate into thebiological unit must be limited to a maximum amount. Both adjunctiveprocesses also use a constant concentration of added infusate, so thatdynamic changes in dose require dynamic changes in injected infusatevolume.

Some embodiments of the present invention incorporate a therapeuticagent 65 with a short half-life into the polymer matrix 55. Because ofthe short time lag from release of the drug from the matrix into thevasculature of the patient, there is increased effectiveness of theshort, half-life agent. Examples of these type of drugs would includeshort acting anesthetic agents such as xylocaine and cardiac agents suchas nitrous oxide derivatives, and prostaglandin derivatives. An operatormay afford effective feedback control of short acting cardiac drugs,analeptics, neurotransmitters, analgesics, or hormones. During themonitoring of an EKG of a patient in the intensive care unit of ahospital, when arrhythmias are detected or cardiac arrest is indicated,a drug can immediately be released into the systemic circulation fortherapy. While monitoring the EEG during anesthesia, drugs can bereleased into the systemic circulation by the present invention todecrease or increase the depth of anesthesia through proper release ofdrugs.

The present invention can be used to administer drug in an automatic,easily controlled manner. Traditional drug regimens have includedadministering drugs orally, sublingually, rectally, subcutaneously,intramuscularly, occularly and parenterally. The regimens with respectto time have included rapid injections, constant rate infusions andcombinations thereof. The present invention can be used to administerdrug or compound when that drug or compound is administered by a tubingor a catheter system. To deliver any arbitrarily administered drugregimen, a computer controller is programmed control energy source 35 toadminister a defined energy magnitude or duration to the tubing matrixof the present invention so that a proportional amount of storedcompound is released into the tubing lumen in a controlled manner. Theease of input profile generation used to control drug release from thepresent inventions, coupled with their potentially complexcharacteristics with respect to time represent a very flexible means ofdrug delivery when traditional methods of drug delivery are considered.A patient can in many instances self-administer the radiation to releasedrug on an “as required” arbitrary basis, e.g. for hypertensiontreatment or for pain relief.

Many natural systems exhibit structure characterized by chaoticbehavior. Various patterns in nature have been described by fractalgeometric curves, surfaces and volumes. There is ample evidence tosuggest that many biological systems incorporate chaotic mechanisms intheir structure. These chaotic structural mechanisms result inobservational data that can be interpreted as fractal in form. Amongmany biological systems, such systems studied have included cardiacfunction and neural stimulation.

Unpredictable changes over time t of a quantity V is known as noiseV(t). The spectral density of V(t), S_(v)(f), gives an estimate of themean square fluctuations of the quantity at a frequency f. As seen inFIG. 13A, by plotting log S_(v)(f) as a function of log f, a slope canbe calculated, and this slope can be interpreted as having a functionalform 1/f^(β), where β is a spectral exponent. Plot 605 of FIG. 13A plotsthe spectral density of a variable where β equal to 1. Graph 610represents the log of the spectral density of a variable for β equal to2. A particular finding has included the discovery that almost allmusical melodies mimic 1/f noise, where 1 is equivalent to “white”noise, and 1/f² corresponds to Brownian motion.

Fractional Brownian motion (fBm) is a mathematical model for many randomfractals found in nature, including 1/f noise. Formally, it is theincrements of fBm (the differences between successive values) thatproduce values corresponding to various 1/f^(β)noise series. Traces offBm are characterized by a parameter H in the range of 0<H<1. The valueH≈0.8 is empirically a good choice for many natural phenomena. FractalBrownian motion has been studied and various methods of generatingtrains of 1-, 2- and 3-dimensional data sets have been developed; see:The Science of Fractal Images, Eds. Heinz-Otto Petigen and DietmarSaupe, 1988. These include spatial approximation methods and,approximation by spectral synthesis. These methods can readily becarried out by ordinary computer analysis. According to anotherembodiment of the present invention, the application of energy to thecatheter assembly is applied according to a 1-dimensional algorithm tosynthesize fBm fractal Brownian motion.

FIG. 7 schematically depicts a system 150 for delivering therapeuticagent in a fractally-based pulsatile manner to a biological unit 30. Anelectronic controller 155 produces a fractally derived signal 157 tocontrol an energy source 35′, such as a laser. Various methods ofgenerating fBm numerical time series can be used to calculatefractally-based signal 157 by controller 155, such as with fast FourierTransform filtering, random midpoint displacement methods, or othermethods described in The Science of Fractal Images, Eds. Heinz-OttoPetigen and Dietmar Saupe, 1988. FIG. 13B-D represent three distinct fBmcurves Vi(t) synthesized using the midpoint displacement method toproduce fBm, where H=0.8. The fractally derived control signal 157 canalso be generated by choosing a value of β preferably between the valuesof 0.5 and 1.5. From selection of either H or β, the log of the spectraldensity of a pulse parameter such as magnitude, duration, and separationinterval can be predicted. FIGS. 13B, 13C, and 13D represent threedistinct fBm curves 620, 630, and 640, respectively, for Vi(t)synthesized using the midpoint displacement method for a selected valueof H. Curve 620 of FIG. 13B represents a fractally derived series oflaser pulse magnitudes at 6 intervals. FIG. 13C represents a series offractally derived laser pulse durations at 6 intervals. FIG. 13Drepresents a series of 6 fractally derived laser pulse spacingintervals. These series have been sampled at regular intervals, Si, todetermine the value of the quantity at the particular sampling time.These value are used to assign values to laser pulse parameters. Eachpulse is characterized by the parameters of pulse magnitude, (V₁),duration, (V₂) and separation interval, (V₃), from the immediatelypreceding pulse in the series, Sp(i).

Numerically, each of these values conforms independently to afractally-based algorithm for each pulse to produce a fractally derived,time domain pulse train signal at the series sampling times as shown inFIG. 13E. A time domain pulse train is shown in FIG. 13E, and issynthesized by combining the pulse series of FIGS. 13B, 13C, and 13D. Asshown in FIG. 13E, there is a first pulse 645 with a magnitude of 5,duration of 5, and an interval spacing of 5 from the origin. A secondpulse 650 from sampling interval 2 has a magnitude of 6, a duration of2, and is spaced 6 units from pulse 645. Pulse 655 has a magnitude of 3,a duration of 3, and is spaced 9 units from pulse 650. The pulse trainrepresented in FIG. 13E represents a model for the laser control signal157. The pulse train of FIG. 13E is scaled by the appropriate intensityand time factors to take into account the specific embodiment of theinvention, considering factors such as the effect of the chosenreleasable compound, the volumetric flow rate of the infusate, the rateat which the particular laser breaks the particular photolabile bonds,and other factors. For example, with certain specific therapeuticagents, the time interval shown could be minutes, where as for otherspecific therapeutic agents the time interval could be hours. As analternate to the method described above, the present inventioncontemplates using the difference between successive magnitudes are usedto assign values to pulse parameters. For example of this alternateembodiment, the difference between successive values of FIGS. 13B, 13C,and 13D would be used to generate the time domain pulse train, insteadof the values themselves.

Compound fractally-based pulse train signals can be obtained bycombining several single pulse series together through superposition andapplying this compound pulse series to derive a fractally based signal157. The signal 157 is provided to energy source 35′ to generate afractally-based stream of energy 160 that enters catheter assembly 20 soas to fracture the bonds between the therapeutic agent and the polymermatrix. These bonds are fractured, and the therapeutic agent issubsequently released in a pulsatile manner. This pulsatile release oftherapeutic agent can include predetermined amounts of agent released atvariable intervals, variable amounts of therapeutic agents released atpredetermined intervals, or variable amounts of therapeutic agentreleased at variable intervals. Since there is a time lag for thetherapeutic agent to defuse out of the polymer matrix and into theinfusate flow stream, and further a time lag for the mixture oftherapeutic agent and infusate to mix within the biological unit, it ispreferable that the frequency content of the pulsed energy 160 be lessthan about 1 Hz.

Since there is evidence that neuronal systems and cardiac systemsexhibit chaotic behavior which can be described in fractal terms, oneembodiment of the present invention administers a drug in a pulsatileinput train, where the pulse separation and/or pulse magnitude relatesto a fractally derived input signal. As one example, the presentinvention contemplates treatment of an acute cardiac event such as heartarrest or fibrillation in an intensive care ward, where intravenoustubing of the present invention would release a therapeutic agent in afractally based pattern to the patient in distress. As another example,the present invention contemplates delivery of intravenous anesthesia,where there is an anesthetic response from a fractally based patterndrug delivery. As another example, the present invention contemplatesthe administration of morphine to a post-operative patient in a fBmpattern. It is anticipated that short acting neurotransmitters or otherpsychoactive agent may be used in this fashion, such as norepinephrine,epinephrine, and dobutamine

On a longer time scale, administration of hormones, such as hGH (humangrowth hormone), can be administered as a fBm pulsatile input to growthdeficient patients.

The delivery of drug or compound therapy using routes other thanparenteral administration in a fBm profile can also be expected toengender beneficial responses when compared to traditional compoundtreatment regimens. Traditional dosage forms which could incorporatethese fractally-based timed release regimens of drug release include,but are not limited to, intramuscular matrix embedded depot,subcutaneous depot injections and various suppository preparations.

Input stimulus other than chemical modifiers when administered as fBmregimens, for example through pulsatile light stimulation to the eye orother non-drug means, may elicit a potentiated or a muted evokedresponse when compared to a steady application of an effector stimuli.Such fBm treatment may include cancer radiation treatments, audiblestimulation or any other stimuli sensed by a living system. Thefrequency content of the pulsed energy can be greater or less than 1 Hz.

It is contemplated that the various embodiments described heretofore arecombinable. For example, the release of compound in a fractally-basedpattern can be incorporated into system 500.

While the invention has been illustrated and described in detail in thedrawings and foregoing description, the same is to be considered asillustrative and not restrictive in character, it being understood thatonly the preferred embodiments have been shown and described and thatall changes and modifications that come within the spirit of theinvention are desired to be protected.

1. A tube including: an interior surface; an exterior surface; a matrixmaterial attached to the interior surface, the matrix including a cavityallowing fluid flow therethrough; and a first compound releasablyattached to the matrix, the matrix being formed from a material havingproperties that cause the first compound to be released from the matrixupon introduction of light energy to the tube.
 2. The tube of claim 1,wherein the first compound is covalently bonded to the matrix.
 3. Thetube of claim 1, wherein the matrix material is formed from a hydrogel.4. The tube of claim 1, further including an optical transmission fiber.5. The tube of claim 4, wherein the optical transmission fiber includesthe interior surface.
 6. The tube of claim 1, wherein the tube isflexible.
 7. The tube of claim 1, wherein the interior surface andexterior surface are opposing sides of a substantially cylindrical wallthat prevents fluid transmission across the wall.
 8. The tube of claim1, wherein the matrix is bonded to the interior surface.
 9. The tube ofclaim 1, further comprising a second compound intermixed in the matrixmaterial with the first compound, said second compound being releasablyattached to the matrix material.
 10. The tube of claim 1, furtherincluding a controller that controls light energy applied to the tube.11. An optical propagation tube including: a substantially cylindricalwall having an interior surface, an exterior surface, and alight-propagating volume therebetween; a matrix material attached to theinterior surface; and a first compound releasably attached to thematrix, the matrix being formed from a material having properties thatcause the first compound to be released from the matrix uponintroduction of light into the tube.
 12. The tube of claim 11, furtherincluding a controller that controls light energy applied to the tube.13. The tube of claim 12, wherein the controller operates control lightenergy applied to the tube in a fractally-based pattern.
 14. The tube ofclaim 11, wherein the matrix material is formed from a hydrogel.
 15. Thetube of claim 11, wherein the first compound is covalently bonded to thematrix material.
 16. The tube of claim 11, further including areflective coating on the exterior surface for reflecting radiation intothe matrix material.
 17. A tube, comprising: a flexible outer sheathhaving an interior surface and an exterior surface; a matrix materialattached to the interior surface of said sheath; a compound releasablycaptured by the molecules of said matrix material; an energy sourcecontrolling the application of energy to the matrix material such thatthe energy, when applied to the matrix material, releases the compoundtherefrom.
 18. The tube of claim 16, wherein the compound is atherapeutic agent.
 19. The tube of claim 16, wherein the compound isreleasably captured by covalent bonding molecules of the compound tomolecules of the matrix material.
 20. The tube of claim 16, wherein theenergy source is configured to release the compound from the matrixmaterial in response to a signal from a cardiac activity sensor receivedby a cardiac monitor.